Raj Srirajaskanthan

Expression of somatostatin and dopamine 2 receptors in neuroendocrine tumours and the potential role for new biotherapies.

Introduction: Somatostatin and dopamine receptors are both G-protein-coupled receptors. Somatostatin receptor (SSTR) expression in neuroendocrine tumours has been well characterised, and there is evidence of dopamine receptor expression in neuroendocrine tumours. In this study, we examined expression of D2R, SSTR-2 and SSTR-5 using immunohistochemistry in patients with neuroendocrine tumours. Methods: Consecutive samples of formalin-fixed paraffin-embedded tumour tissue were available from 56 patients with a histologically confirmed diagnosis of neuroendocrine tumour (NET). The study population was divided into low-grade (n = 29), intermediate-grade (n = 18) and high-grade NET (n = 9). Immunohistochemical evaluation was performed for the expression of SSTR-2a, SSTR-5 and D2 receptors (D2R). Results: Both SSTR-2 and SSTR-5 were expressed in 100% of low-grade, 94.4% of intermediate-grade and 66.7% of high-grade NET. D2R was expressed in 93.1% of low-grade, 77.8% of intermediate-grade and 44.4% of high-grade tumours. Co-expression of all 3 receptors was present in 93.1% of low-grade tumours. There was an inverse correlation of SSTR-2 (r = –0.380, p < 0.005) and SSTR-5 (r = –0.472, p < 0.0001) with tumour grade. D2R was positively correlated with SSTR-2 (r = 0.269, p = 0.041) and SSTR-5 (r = 0.267, p = 0.045). Also, D2R expression was inversely correlated with grade of tumour (r = 0.395, p = 0.006). Octreoscan correlated with SSTR-2, SSTR-5 and D2R expression. Conclusion: D2R is expressed in the majority of low and intermediate grade tumours. It is co-expressed with SSTR-2 and SSTR-5 in the majority of cases. The advent of new chimeric molecules that bind both somatostatin and dopamine receptors may provide a new therapeutic option in the management of neuroendocrine patients.

Review article: the investigation and management of rectal neuroendocrine tumours

Gastric carcinoids (GCs) or neuroendocrine tumours (NETs) are increasingly identified at endoscopy, and account for 0.6–2% of all gastric polyps identified. The SEER database in the US has demonstrated a rising incidence of gastric NETs amongst all NETs; from 2.2% between 1950 and 1969 to 6.0% between 2000 and 2007.

Long-term results of patients with malignant carcinoid syndrome receiving octreotide LAR.

Background  Octreotide LAR is an established treatment for malignant carcinoid syndrome. However, studies with large number of patients and long follow‐up are lacking.

A review of thymic tumours

Tumours of the thymus are uncommon and are generally regarded as being indolent. Whilst this is often true of thymomas; thymic adenocarcinoma and thymic neuroendocrine cancer can be aggressive and have a poor prognosis. Understanding the biology of these tumours is important for prognosis and management. The pathological features of these tumours are examined in detail. Imaging modalities for aiding in diagnosis and staging of these tumours are described; this includes CT and MRI, plus more recent advances including the use of FDG-PET and Indium-111 Octreotide scintigraphy. The treatment options available including curative surgery, debulking surgery, chemotherapy, somatostatin analogues and peptide receptor radionuclide therapy are discussed. The optimal chemotherapy regimens are still unclear, although promising results have been obtained with platinum-based chemotherapy. The role for adjuvant therapy in both thymic carcinoma and thymoma is unclear except, in patients with stage I thymomas. There is a high expression of somatostatin receptors in thymic tumours and anti-tumour benefit has been reported in patients treated with somatostatin analogues. A new development is the role of peptide receptor radionuclide therapy. This has become an established therapy in management of gastroenteropancreatic neuroendocrine tumours and its use has been recently described in case reports in both thymoma and thymic carcinoma.

Circulating angiopoietin-2 is elevated in patients with neuroendocrine tumours and correlates with disease burden and prognosis

Angiogenesis is an essential process in the development and growth of tumours. There are a large number of angiogenic mediators including the angiopoietin (Ang) family and vascular endothelial growth factor, which play an important role in both physiological and pathological angiogenesis. This study examines serum levels of Ang-1 and Ang-2 in patients with neuroendocrine tumour (NET) compared healthy controls. ELISA for Ang-1 and Ang-2 was performed in 47 patients with histologically proven NETs and 44 healthy controls. Immunohistochemical staining for Ang-2 was performed in patients to demonstrate cellular location of Ang-2. Serum Ang-2 levels were significantly elevated in patients compared controls (median 4756 vs 2495 pg/ml, P<0.001), while there was no significant difference in Ang-1 levels. The ratio of Ang-2:Ang-1 was significantly elevated in patients compared controls (0.13 vs 0.066, P<0.001). Serum Ang-2 levels were significantly elevated in patients with distant metastases compared with those without metastasis (median 5080 vs 3360 pg/ml, P=0.01). There was also a significant increase between Ang-2 levels and volume of liver metastases (P=0.014). Time to disease progression was worse in patients with serum Ang-2 levels >4756 pg/ml (P=0.04). Serum Ang-2 but not Ang-1 is elevated in NET patients. Ang-2 may be a useful serum marker for monitoring and assessment of prognosis in patients with NETs.

Surgical management and palliative treatment in bronchial neuroendocrine tumours: a clinical study of 45 patients.

Bronchial neuroendocrine tumours account for 1-2% of all lung cancers; they are thought to arise from the neuroendocrine cells located in the bronchial mucosa. The majority of the literature available comprises surgical series and there is a scarcity of data available for the management of patients with inoperable disease. We present a series of 45 patients referred to our institution from 1998 to 2006, with a mean follow-up of 54 months. Histological diagnosis from our department was available for 39 patients, with the remainder having had histological assessment performed previously. Typical carcinoid was present in 25 cases, atypical in 9 cases, large cell neuroendocrine carcinoma in 4 and 1 case of small cell lung carcinoma. All patients were staged at time of initial diagnosis with CT scan, in addition Octreoscans were performed when appropriate. Twenty-six of these 45 cases had unresectable disease, whilst the remainder were treated with surgical resection. Initial therapy with surgical resection was performed in 19 patients, 2 of whom had undergone neo-adjuvant chemotherapy. Recurrence occurred in 7 (36.8%), average duration of disease-free survival post-surgery was 61 months. Chemotherapy was first line therapy in five cases, four achieved disease stabilization and one case had progressive disease. Somatostatin analogues were used as first line therapy in six patients, for symptom control and anti-tumour effect. Peptide receptor radionuclide therapy, with Yttrium-90 DOTA-Octreotate, was given in two cases, both of whom achieved disease stabilization for 9-12 months respectively. There was a significant difference between Stage 4 and Stage 1 disease at presentation and survival. In conclusion curative surgical resection is treatment of choice, however, chemotherapy, somatostatin analogues and peptide receptor radionuclide therapy offers palliation improving both symptoms and mortality.

α-Fetoprotein and human chorionic gonadotrophin-β as prognostic markers in neuroendocrine tumour patients

Serum chromogranin A is the most useful general and prognostic tumour marker available for neuroendocrine tumour (NET) patients. The role of other tumour markers is less clear. In order to determine the diagnostic and prognostic value of serum α-fetoprotein (AFP) and human chorionic gonadotrophin-β (hCGβ) in NETs, a database containing biochemical, histological, and survival data on 360 NET patients was constructed. This data was statistically assessed, using Statistical Package for the Social Sciences, to determine the utility of commonly measured tumour markers with particular emphasis on AFP and hCGβ. α-Fetoprotein and hCGβ were raised in 9.5 and 12.3% of patients respectively and jointly raised in 9.1% of patients in whom it was measured. α-Fetoprotein levels associated strongly and positively with tumour grade, serum CgA and hCGβ levels, and worse survival. Human chorionic gonadotrophin-β levels also associated strongly and positively with serum CgA and AFP levels, and worsening survival. α-Fetoprotein and hCGβ are elevated in high-grade NETs, with a rapidly progressive course and poorer survival. They also correlate with chromogranin-A, which is known to be a marker of tumour burden and to have prognostic value. Thus AFP and hCGβ are clinically important in NETs and when elevated are poor prognostic markers.

Review article : future therapies for management of metastatic gastroenteropancreatic neuroendocrine tumours

Background  Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are relatively uncommon tumours that occur anywhere within the gastrointestinal tract. The prevalence of GEP NETs is estimated to be 35 per 100 000 population. Patients often present with metastatic disease and consequently, palliative treatments form the mainstay of therapy.

ENETS TNM Staging Predicts Prognosis in Small Bowel Neuroendocrine Tumours

Introduction. Small bowel neuroendocrine tumours (NETs) are the most common type of gastrointestinal neuroendocrine tumours. The incidence and prevalence of these tumours are on the rise. The aims of this study were to determine prognostic clinicopathological features and whether the ENETS TNM staging system predicts prognosis and also. Method. Clinical data was collected retrospectively from 138 patients with histologically proven small bowel NETs managed at Kings College Hospital. Histology was reviewed and small bowels tumours, were staged according to the ENETS TNM staging system. Results. Median age was 65 years (range 29–87). The 5-year survival was 79.5% and the 10-year survival was 48.5%. Resection of the primary tumour was associated with improved survival (120 versus 56 months, P < 0.05). On multivariate analysis prognostic factors were primary tumour resection and not having a carcinoid heart disease. TNM staging significantly separated survival of stage 2 and stage 3 from stage 4 NETs. Conclusion. Small bowel primary tumour resection and not having carcinoid heart disease are prognostic factors. The ENETS TNM staging and grading system appears to be of prognostic relevance to small bowel NETs.

Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges–Lehmann estimators of median treatment differences from placebo of −54.0% (95% confidence limits, −85.0%, −25.1%, P < 0.001) and −89.7% (95% confidence limits, −113.1%, −63.9%, P < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659).